Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sodium-activated potassium KNa channels Slack and Slick are encoded by KCNT1 and KCNT2, respectively. These channels are found in neurons throughout the brain, and are responsible for a delayed outward current termed I KNa. These currents integrate into shaping neuronal excitability, as well as adaptation in response to maintained stimulation. Abnormal Slack channel activity may play a role in Fragile X syndrome, the most common cause for intellectual disability and inherited autism. Slack channels interact directly with the fragile X mental retardation protein (FMRP) and I KNa is reduced in animal models of Fragile X syndrome that lack FMRP. Human Slack mutations that alter channel activity can also lead to intellectual disability, as has been found for several childhood epileptic disorders. Ongoing research is elucidating the relationship between mutant Slack channel activity, development of early onset epilepsies and intellectual impairment. This review describes the emerging role of Slack channels in intellectual disability, coupled with an overview of the physiological role of neuronal I KNa currents.
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PMID:Emerging role of the KCNT1 Slack channel in intellectual disability. 2512 Apr 33

Fragile X mental retardation protein (FMRP) is an RNA-binding protein that has a major effect on neuronal protein synthesis. Transcriptional silencing of the FMR1 gene leads to loss of FMRP and development of Fragile X syndrome (FXS), the most common known hereditary cause of intellectual impairment and autism. Here we utilize SILAC-based quantitative phosphoproteomics to analyze murine FMR1(-) and FMR1(+) fibroblastic cell lines derived from FMR1-KO embryos to identify proteins and phosphorylation sites dysregulated as a consequence of FMRP loss. We quantify FMRP-related changes in the levels of 5,023 proteins and 6,133 phosphorylation events and map them onto major signal transduction pathways. Our study confirms global downregulation of the MAPK/ERK pathway and decrease in phosphorylation level of ERK1/2 in the absence of FMRP, which is connected to attenuation of long-term potentiation. We detect differential expression of several key proteins from the p53 pathway, pointing to the involvement of p53 signaling in dysregulated cell cycle control in FXS. Finally, we detect differential expression and phosphorylation of proteins involved in pre-mRNA processing and nuclear transport, as well as Wnt and calcium signaling, such as PLC, PKC, NFAT, and cPLA2. We postulate that calcium homeostasis is likely affected in molecular pathogenesis of FXS.
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PMID:Quantitative phosphoproteomics of murine Fmr1-KO cell lines provides new insights into FMRP-dependent signal transduction mechanisms. 2516 79

Adolescents and adults with an autism spectrum disorder (ASD) who do not have an intellectual impairment or disability (ID), described here as individuals with high-functioning autism spectrum disorder (HFASD), represent a complex and underserved psychiatric population. While there is an emerging literature on the mental health needs of children with ASD with normal intelligence, we know less about these issues in adults. Of the few studies of adolescents and adults with HFASD completed to date, findings suggest that they face a multitude of cooccurring psychiatric (e.g., anxiety, depression), psychosocial, and functional issues, all of which occur in addition to their ASD symptomatology. Despite this, traditional mental health services and supports are falling short of meeting the needs of these adults. This review highlights the service needs and the corresponding gaps in care for this population. It also provides an overview of the literature on psychiatric risk factors, identifies areas requiring further study, and makes recommendations for how existing mental health services could include adults with HFASD.
Autism Res Treat 2014
PMID:Mental health services for individuals with high functioning autism spectrum disorder. 2527 25

Comorbid psychiatric Disorders are seen commonly in people with intellectual disability and in fact they are at greater risk for developing other health disorders. Most prevalent chronic health conditions in children with intellectual disability are epilepsy, cerebral palsy,anxiety disorders, sleep disorders and autism spectrum disorders. Co morbidities multiply the problem of people with intellectual impairment to a great extent and hence an accurate psychological assessment of multiple diagnoses is useful in detecting the specific underlying processes differentiating the co morbid syndrome and in planning an appropriate management and rehabilitation program. This case report is presented to emphasize the fact that though. It is common for intellectually disabled children to have other co-morbid psychiatric disorders, it is important to have accurate, suitable assessment and recording of every co-morbid disorder as it has its own implication in course and outcome of the disability in the child. A comprehensive management approach involving people from various spheres would be required to improve the quality of life and for reduction of burden of care giver.We describe a child of intellectual disability with multiple co morbidities.
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PMID:Intellectual disability and multiple co morbid psychiatric disorders in a child: a case report. 2558 92

In the absence of intellectual impairment, girls are diagnosed with autism spectrum disorder significantly less and later than boys. This study explored potential reasons for why autism spectrum disorder may be more difficult to identify in girls, based on carer concerns during the pre-diagnosis period. Carers of 92 boys and 60 girls diagnosed with autism spectrum disorder from school age completed an online survey addressing concerns regarding the child's development during the pre-school years (pre-diagnosis). Significant sex differences were evident in key early concerns, as well as the strategies used to navigate pre-school social situations, and the types of restricted interests. Findings suggest, from carer perspective, that girls who went on to be diagnosed with autism spectrum disorder presented differently when compared to boys, providing insight into why the diagnosis of autism spectrum disorder may be more difficult to make with cognitively able girls.
Autism 2016 Jan
PMID:Sex differences in pre-diagnosis concerns for children later diagnosed with autism spectrum disorder. 2571 30

CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.
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PMID:CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. 2573 78

Fragile X Syndrome (FXS) is the most common heritable form of intellectual impairment as well as the leading monogenetic cause of autism. In addition to its canonical definition as a neurodevelopmental disease, recent findings in the clinic suggest that FXS is a systemic disorder that is characterized by a variety of heterogeneous phenotypes. Efforts to study FXS pathogenesis have been aided by the development and characterization of animal models of the disease. Research efforts in Drosophila melanogaster have revealed key insights into the mechanistic underpinnings of FXS. While much remains unknown, it is increasingly apparent that FXS involves a myriad of spatially and temporally specific alterations in cellular function. Consequently, the literature is filled with numerous discordant findings. Researchers and clinicians alike must be cognizant of this dissonance, as it will likely be important for the design of preclinical studies to assess the efficacy of therapeutic strategies to improve the lives of FXS patients.
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PMID:Deciphering discord: How Drosophila research has enhanced our understanding of the importance of FMRP in different spatial and temporal contexts. 2602 73

The controversies that have arisen in endeavoring to establish the nature of the relationships between autism and epilepsy might be summarized in a few simple questions, most of which do not yet have clear, complete answers. Does epilepsy cause autism? Does autism cause epilepsy? Are there underlying brain mechanisms that predispose to both conditions? What is the role of genetics in this regard? What is the importance of prenatal, perinatal, and postnatal environmental factors? Do any of the proposed relationships between autism and epilepsy provide insight into useful management or treatment? Is the prognosis of either autism or epilepsy different when the other condition is also present? What is the role of additional comorbidities, such as intellectual impairment or attention deficit hyperactivity disorder, in the relationship between the two conditions and in influencing treatment choices? From the evidence currently available, it would appear that epilepsy can rarely be the cause of autistic features but is not the cause of autism in most cases. There is currently no credible mechanism for suggesting that autism might cause epilepsy. There is strong evidence for an underlying predisposition for both conditions, particularly arising from genetic investigations. However, many issues remain unresolved. Considering the amount of research that has been published in this area, it is surprising that so few definitive answers have been established. The papers in this issue's special section provide additional insights into the relationships between autism and epilepsy; while they do not provide answers to all the questions, they represent considerable progress in this area and, at the very least, give some strong indication of what research might, in the future, provide such answers.
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PMID:Current controversies in the relationships between autism and epilepsy. 2744 15

Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder affecting nearly one in 5000 newborn males and is a leading genetic cause of autism spectrum disorder. In addition to developmental delays and intellectual impairment, FXS is characterized by seizures, attention deficit, and hypersensitivity to visual, tactile and auditory stimuli. The Fmr1 gene encodes Fragile X mental retardation protein (FMRP), which is abundant in neurons, binds select mRNAs and functions as a negative regulator of mRNA translation. A deficiency in FMRP, as in FXS and Fmr1 knockout (KO) animals, results in neuronal dysmorphology and altered synaptic function. Additionally, there is evidence for disruption of GABAergic circuits in subjects lacking FMRP. Our previous studies demonstrated widespread expression of FMRP in human auditory brainstem neurons. Given this observation, we hypothesized that FMRP is highly expressed in rat auditory brainstem neurons and that the auditory hypersensitivity characteristic of FXS results from dysfunction of brainstem networks secondary to decreased expression of FMRP. In our investigation of postnatal day 50 (P50) control rats, we found that FMRP was widely expressed in neurons of the superior olivary complex (SOC). In P50 Fmr1 KO rats, many SOC neurons had a smaller soma when compared to controls, indicative of abnormal neuronal morphology. Additionally, neurons in the medial superior olive (MSO) were more round in Fmr1 KO rats. There was also reduced expression of glutamic acid decarboxylase (GAD67) in neurons of the superior paraolivary nucleus (SPON) and a reduction in the number of calretinin-immunoreactive terminals associated with neurons of the medial nucleus of the trapezoid body (MNTB). Together, these findings support the conclusion that the auditory dysfunction characteristic of FXS arises, at least in part, from defective brainstem networks.
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PMID:Abnormal neuronal morphology and neurochemistry in the auditory brainstem of Fmr1 knockout rats. 2616 28

Young adults with ASD and no intellectual impairment are more likely to exhibit clinical levels of anxiety than typically developing peers (DSM-5, American Psychiatric Association, 2013). This study tests a mechanistic model in which anxiety culminates via emotion dysregulation and social motivation. Adults with ASD (49 males, 20 females) completed self-report measures on emotion regulation, caregivers completed measures on ASD severity and both on social anxiety. Results indicated that emotion dysregulation (p < .001; p < .05) and social motivation (p < .05, p < .001) significantly predicted social anxiety as reported by caregivers and young adults respectively. However, social motivation did not appear to play a moderating role in the relationship between emotion regulation and anxiety, even when controlling for social awareness. Significant predictor variables of social anxiety varied based on reporter (i.e. caregiver versus young adult), with difficulty engaging in goal-directed behaviors during negative emotions serving as the only shared predictor.
J Autism Dev Disord 2015 Dec
PMID:Emotion Dysregulation and Anxiety in Adults with ASD: Does Social Motivation Play a Role? 2631 54


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